Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Prematurely born babies are often treated with glucocorticoids. We studied the consequences of an early postnatal and short dexamethasone treatment (0.1–0.01 μg/g, days 1–4) on lung development in rats, focusing on its influence on peaks of cell proliferation around day 4 and of programmed cell death at days 19–21. By morphological criteria, we observed a dexamethasone-induced premature maturation of the septa ( day 4), followed by a transient septal immatureness and delayed alveolarization leading to complete rescue of the structural changes. The numbers of proliferating (anti-Ki67) and dying cells (TdT-mediated dUTP nick end labeling) were determined and compared with controls. In dexamethasone-treated animals, both the peak of cell proliferation and the peak of programmed cell death were reduced to baseline, whereas the expression of tissue transglutaminase (transglutaminase-C), another marker for postnatal lung maturation, was not significantly altered. We hypothesize that a short neonatal course of dexamethasone leads to severe but transient structural changes of the lung parenchyma and influences the balance between cell proliferation and cell death even in later stages of lung maturation.

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Cytosolic Guanine Nucledotide Binding Deficient Form of Transglutaminase 2 (R580a) Potentiates Cell Death in Oxygen Glucose Deprivation

PLoS ONE ◽

10.1371/journal.pone.0016665 ◽

2011 ◽

Vol 6 (1) ◽

pp. e16665 ◽

Cited By ~ 24

Author(s):

Gozde Colak ◽

Jeffrey W. Keillor ◽

Gail V. W. Johnson

Keyword(s):

Cell Death ◽

Transglutaminase 2 ◽

Glucose Deprivation ◽

Oxygen Glucose Deprivation

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Importance of Tissue Transglutaminase in Repair of Extracellular Matrices and Cell Death of Dermal Fibroblasts After Exposure to a Solarium Ultraviolet A Source

Journal of Investigative Dermatology ◽

10.1046/j.1523-1747.2003.12353.x ◽

2003 ◽

Vol 121 (2) ◽

pp. 412-423 ◽

Cited By ~ 26

Author(s):

Stephane R. Gross ◽

Zita Balklava ◽

Martin Griffin

Keyword(s):

Cell Death ◽

Tissue Transglutaminase ◽

Dermal Fibroblasts ◽

Extracellular Matrices ◽

Ultraviolet A

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Comparison of tissue transglutaminase 2 and bone biological markers osteocalcin, osteopontin and sclerostin expression in human osteoporosis and osteoarthritis

Amino Acids ◽

10.1007/s00726-016-2290-4 ◽

2016 ◽

Vol 49 (3) ◽

pp. 683-693 ◽

Cited By ~ 8

Author(s):

Chiara Tarquini ◽

Rosanna Mattera ◽

Francesca Mastrangeli ◽

Sara Agostinelli ◽

Amedeo Ferlosio ◽

...

Keyword(s):

Biological Markers ◽

Tissue Transglutaminase ◽

Transglutaminase 2

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Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells

Molecular and Cellular Biology ◽

10.1128/mcb.14.10.6584-6596.1994 ◽

1994 ◽

Vol 14 (10) ◽

pp. 6584-6596

Author(s):

G Melino ◽

M Annicchiarico-Petruzzelli ◽

L Piredda ◽

E Candi ◽

V Gentile ◽

...

Keyword(s):

Cell Death ◽

Structural Changes ◽

Tissue Transglutaminase ◽

Neuroblastoma Cell ◽

Neuroblastoma Cells ◽

Neuroblastoma Cell Line ◽

Human Neuroblastoma Cell ◽

Human Neuroblastoma ◽

Transfected Cells ◽

Protein Levels

In this report, we show that the overexpression of tissue transglutaminase (tTG) in the human neuroblastoma cell line SK-N-BE(2) renders these neural crest-derived cells highly susceptible to death by apoptosis. Cells transfected with a full-length tTG cDNA, under the control of a constitutive promoter, show a drastic reduction in proliferative capacity paralleled by a large increase in cell death rate. The dying tTG-transfected cells exhibit both cytoplasmic and nuclear changes characteristic of cells undergoing apoptosis. The tTG-transfected cells express high Bcl-2 protein levels as well as phenotypic neural cell adhesion molecule markers (NCAM and neurofilaments) of cells differentiating along the neuronal pathway. In keeping with these findings, transfection of neuroblastoma cells with an expression vector containing segments of the human tTG cDNA in antisense orientation resulted in a pronounced decrease of both spontaneous and retinoic acid (RA)-induced apoptosis. We also present evidence that (i) the apoptotic program of these neuroectodermal cells is strictly regulated by RA and (ii) cell death by apoptosis in the human neuroblastoma SK-N-BE(2) cells preferentially occurs in the substrate-adherent phenotype. For the first time, we report here a direct effect of tTG in the phenotypic maturation toward apoptosis. These results indicate that the tTG-dependent irreversible cross-linking of intracellular protein represents an important biochemical event in the induction of the structural changes featuring cells dying by apoptosis.

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Cell cycle kinetics, tissue transglutaminase and programmed cell death (apoptosis)

FEBS Letters ◽

10.1016/0014-5793(92)81392-y ◽

1992 ◽

Vol 311 (2) ◽

pp. 174-178 ◽

Cited By ~ 29

Author(s):

S. El Alaoui ◽

S. Mian ◽

J. Lawry ◽

G. Quash ◽

M. Griffin

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Programmed Cell Death ◽

Tissue Transglutaminase ◽

Cell Cycle Kinetics

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Abstract 269: Exendin-4 Prevents Glucose-induced Secretion of Tissue Transglutaminase-2 from Cardiac Microvascular Endothelial Cells: Potential Role in the Prevention of Matrix Remodeling in Diabetes

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.269 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Ali S Shihab ◽

Vanitra A Richardson ◽

Betsy B Dokken

Keyword(s):

Endothelial Cells ◽

Protein Expression ◽

High Glucose ◽

Tissue Transglutaminase ◽

Vascular Complications ◽

Transglutaminase 2 ◽

Conditioned Media ◽

Microvascular Endothelial Cells ◽

Microvascular Endothelial ◽

Cardiac Microvascular Endothelial Cells

Diabetes causes endothelial dysfunction, which is the initial trigger for vascular complications in diabetic patients. Hyperglycemia initiates a cascade of events that alters protein expression and secretion by endothelial cells. Tissue transglutaminase-2 (tTG2) is an enzyme that under physiologic conditions is sequestered inside the endothelial cell, but under pathologic conditions causing decreased bioavailability of nitric oxide, tTG2 is secreted, activated, and catalyzes irreversible crosslinking of proteins in the extracellular matrix (ECM). Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist, used in the treatment of type 2 diabetes, which has vasculo-protective effects. We hypothesized that hyperglycemic stress would induce secretion of tTG2, and that this effect would be attenuated by Ex-4. Mouse cardiac microvascular endothelial cells (MCECs) were serum-starved and exposed to control (5.5 mM glucose) or hyperglycemic (25 mM glucose) conditions, with or without Ex-4 (10 nM) x 72 hrs. Proteins from conditioned media were isolated, trypsinized, and analyzed using LC-MS/MS (LTQ Orbitrap Velos). Immunoblots from cell homogenate were probed for tTG protein expression. Conditioned media from MCECs exposed to high-glucose but not Ex-4 contained tTG2, which was absent in media from cells exposed to high-glucose and Ex-4, as well as in media from control cells, suggesting that Ex-4 prevented the secretion of tTG2 induced by hyperglycemic stress. Protein expression in cell lysate was not different. These findings may have important implications for the etiology of diabetic vascular complications, and for the role of Ex-4 to prevent the pathologic ECM remodeling associated with diabetic vasculopathy. Further studies are ongoing to determine the mechanisms of glucose-induced secretion of tTG2, as well as the mechanisms by which Ex-4 prevents this effect.

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Stem cell factor and leukemia inhibitory factor promote primordial germ cell survival by suppressing programmed cell death (apoptosis)

Development ◽

10.1242/dev.118.4.1089 ◽

1993 ◽

Vol 118 (4) ◽

pp. 1089-1094 ◽

Cited By ~ 8

Author(s):

M. Pesce ◽

M.G. Farrace ◽

M. Piacentini ◽

S. Dolci ◽

M. De Felici

Keyword(s):

Cell Death ◽

Stem Cell ◽

Programmed Cell Death ◽

Leukemia Inhibitory Factor ◽

Stem Cell Factor ◽

Tissue Transglutaminase ◽

Primordial Germ Cell ◽

Inhibitory Factor ◽

High Level

Proliferating primordial germ cells (PGCs) isolated from mouse embryos soon after their arrival in the genital ridges would only survive in vitro at temperature of less than 30 degrees C (De Felici, M. and McLaren, A. (1983). Exp. Cell. Res. 144, 417–427; Wabik-Sliz, B. and McLaren, A. (1984). Exp. Cell. Res. 154, 530–536) or when co-cultured on cell feeder layers (Donovan, P. J., Stott, D., Godin, I., Heasman, J. and Wylie, C. C. (1986). Cell 44, 831–838; De Felici, M. and Dolci, S. (1991). Dev. Biol. 147, 281–284). In the present paper we report that mouse PGC death in vitro occurs with all the hallmarks of programmed cell death or apoptosis. We found that after 4–5 hours in culture many PGCs isolated from 12.5 dpc fetal gonads assumed a nuclear morphology and produced membrane bound fragments (apoptotic bodies) typical of apoptotic cells. In addition, PGCs in culture accumulated high level of tissue transglutaminase (tTGase; an enzyme that is induced and activated during apoptosis) and showed extensive degradation of DNA to oligonucleosomal fragments, which is characteristic of apoptosis. The physiological relevance of this mechanism of PGC death is supported by the finding that some PGCs undergoing apoptosis, as revealed by the high level of tTGase expression, were detected in the embryo. Most importantly, we show that the addition of stem cell factor (SCF) or leukemia inhibitory factor (LIF) to the culture medium, two cytokines known to favour PGC survival and/or proliferation in vitro, markedly reduced the occurrence of apoptosis in PGCs during the first hours in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

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